Structural and biochemical characterization of Class I and Class III adenylyl cyclases from microbial pathogens

腺苷酸环化酶（ACs）从ATP合成无处不在的第二信使环AMP （cAMP）。在病原微生物中，cAMP常参与毒力机制的调控。微生物含有I类和III类亚科的AC酶。一些结构上研究得很好的III类微生物ACs已被证实为药物靶点，并且该家族的低保守性使得对单个III类酶的特异性抑制成为可能。目前还没有AC I类的结构信息，这是细菌有机体所特有的，因此可以对细菌病原体的信号系统进行更特异性的抑制。我们建议研究区分CyaB的结构细节，CyaB是病原菌绿脓杆菌（Pseudomonas aeroginosa）的一个确定的药物靶点，与它的人类宿主的III类ACs。利用这些信息，改进现有抑制剂以及全新化合物的修饰将被确定。此外，我们建议解决一类AC的第一个晶体结构，作为这个保守家族的代表。结构数据将再次用于抑制剂的开发，这将导致药物只影响I类携带ac的病原体，对人类宿主的副作用很小。

Adenylyl cyclases (ACs) synthesize the ubiquitous second messenger cyclic AMP (cAMP) from ATP. In pathogenic microbes, cAMP is often involved in the regulation of virulence mechanisms. Microbes contain AC enzymes of the Class I and Class III subfamilies. Several microbial ACs of the structurally well studied Class III have been confirmed as drug targets, and the low conservation within this family renders specific inhibition of individual Class III enzymes possible. No structural information is yet available for the AC Class I, which is unique to bacterial organisms and thus enables even more specific inhibition of signaling systems of bacterial pathogens.We propose to study the structural details that differentiate CyaB, a confirmed drug target in the pathogen Pseudomonas aeroginosa, from Class III ACs of its human host. Using this information, modifications improving existing inhibitors as well as completely novel compounds will be identified. Further, we propose to solve the first crystal structure of a Class I AC as a representative of this conserved family. The structural data will again be used for the development of inhibitors, which should result in drugs affecting only the Class I AC-carrying pathogen with little side effects on the human host.